This study will compare the activity of the combination of savolitinib and osimertinib against the combination of savolitinib with placebo to osimertinib in patients with Epidermal Growth Factor Receptor Mutation Positive and MET amplified, locally advanced or metastatic non-small cell lung cancer who have progressed following treatment with osimertinib.
Name: Osimertinib + Savolitinib
Name: Savolitinib + Placebo
Description: ORR will be performed based on Investigator assessment of disease progression by RECIST 1.1.
Measure: Objective Response Rate (ORR) Time: The primary analysis will occur 6 months after the last patient is randomised.Description: PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by the investigator or death due to any cause.
Measure: Progression-free Survival (PFS) Time: The primary analysis will occur 6 months after the last patient is randomised.Description: DoR is defined as the time from the date of first documented response until date of documented progression per RECIST 1.1 as assessed by the investigator or death in the absence of disease progression.
Measure: Duration of Response (DoR) Time: The primary analysis will occur 6 months after the last patient is randomised.Description: TSA is defined as the percentage change from baseline in TLs at 12 weeks per RECIST 1.1 as assessed by the investigator.
Measure: Tumour Size Assessment (TSA) Time: The primary analysis will occur 6 months after the last patient is randomised.Description: OS is defined as time from randomisation until the date of death due to any cause.
Measure: Overall Survival (OS) Time: The primary analysis will occur 6 months after the last patient is randomised. the final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died.Description: Objective response rate in patients who cross over after progression on savolitinib plus placebo, defined as the proportion of patients with measurable disease who have a CR or PR as determined by the investigator at the local site per RECIST 1.1.
Measure: Objective Response Rate (ORR) Time: The primary analysis will occur 6 months after the last patient is randomised. the final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died.Description: Progression free survival in patients who cross over after progression on savolitinib plus placebo, defined as time from the first dose in the cross over period until progression per RECIST 1.1 as assessed by the investigator or death due to any cause.
Measure: Progression Free Survival Time: The primary analysis will occur 6 months after the last patient is randomised. the final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died.Description: Duration of response in patients who cross over after progression on savolitinib plus placebo, defined as the time from the date of first documented response during the cross-over period until date of documented progression per RECIST 1.1 as assessed by the investigator or death in the absence of disease progression.
Measure: Duration of Response Time: The primary analysis will occur 6 months after the last patient is randomised. the final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died.Description: Tumour size assessment in patients who cross over after progression on savolitinib plus placebo, defined as the percentage change from baseline in TLs at 12 weeks per RECIST 1.1 as assessed by the investigator.
Measure: Tumour Size Assessment Time: The primary analysis will occur 6 months after the last patient is randomised. the final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died.Description: To determine the prevalence of ctDNA clearance after savolitinib plus osimertinib or savolitinib plus placebo treatment in this patient population
Measure: Total clearance in EGFR mutations at 6-weeks after therapy initiation (percentage and absolute change from baseline in EGFR mutation allele frequencies). Time: The primary analysis will occur 6 months after the last patient is randomised.Description: To evaluate the PK of savolitinib and osimertinib.
Measure: Plasma concentrations of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib) Time: Cycle 1, Day 1: Pre-dose and 1 and 3 hours post-dose; Cycle 2, Day 1: Pre-dose and 1 and 3 hours post-dose; Cycle 3, Day 1: Pre dose and 1, 3, 4, and 6 hours post-dose; Cycles 6 and 11, Day 1: Pre-dose only. (Each Cycle is 28 days).Description: To evaluate the PK of savolitinib and osimertinib.
Measure: Time dependency of the PK of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib) Time: C3h Cycle 2 Day 1/C3h Cycle 1 Day 1; Cpre-dose Cycle 3 Day 1/Cpre-dose Cycle 2 Day 1; Cpre-dose Cycle 6 Day 1/Cpre-dose Cycle 2 Day 1; Cpre-dose Cycle 11 Day 1/Cpre-dose Cycle 2 Day 1. (Each Cycle is 28 days)Description: To evaluate the PK of savolitinib and osimertinib.
Measure: AUCss of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib) Time: Cycle 3, Day 1 (Each Cycle is 28 days)Description: To evaluate the PK of savolitinib and osimertinib.
Measure: Cssmax of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib) Time: Cycle 3, Day 1 (Each Cycle is 28 days)Description: To evaluate the PK of savolitinib and osimertinib.
Measure: Tssmax of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib) Time: Cycle 3, Day 1 (Each Cycle is 28 days)Description: To evaluate the PK of savolitinib and osimertinib.
Measure: CLss/F of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib) Time: Cycle 3, Day 1 (Each Cycle is 28 days)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number and percentage of subjects with adverse events (AEs) in different categories: All AEs Time: Continuous collection from First dose until study termination, on average 12 monthsDescription: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number and percentage of subjects with adverse events (AEs) in different categories: Serious AEs Time: Continuous collection from First dose until study termination, on average 12 monthsDescription: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number and percentage of subjects with adverse events (AEs) in different categories: Causally related AEs Time: Continuous collection from First dose until study termination, on average 12 monthsDescription: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number and percentage of subjects with adverse events (AEs) in different categories: Discontinuations due to AEs Time: Continuous collection from First dose until study termination, on average 12 monthsDescription: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number and percentage of subjects with adverse events (AEs) in different categories: Deaths Time: Continuous collection from First dose until study termination, on average 12 monthsDescription: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Albumin Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Alkaline phosphatase Time: Screening, weekly for first 5, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in ALT Time: Screening, weekly for first 10, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Amylase Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in AST Time: Screening, weekly for first 10 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation(an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Total bilirubin Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Total Calcium Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Creatinine Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Glucose Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation(an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Magnesium Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Sodium Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Potassium Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Total Protein Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in BUN or urea Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Lactate dehydrogenase Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Haematocrit Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Haemoglobin Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Leucocyte cell count Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Platelet count Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Red blood cell count Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Reticulocytes Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Neutrophil count Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Lymphocyte count Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.
Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Eosinophil count Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)Description: To collect and store germline DNA for exploration of the role of HLA alleles in developmental toxicity.
Measure: HLA alleles associated with susceptibility to drug related AEs (such as but not limited to hypersensitivity). Time: On Cycle 1 Day 1 only (each cycle is 28 days)Description: Defined as time from randomisation until the date of death due to any cause
Measure: Overall survival, in patients who cross over after progression on savolitinib plus placebo Time: The primary analysis will occur 6 months after the last patient is randomised. The final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died.Allocation: Randomized
Parallel Assignment
There is one SNP
All genders are permitted - Histologically or cytologically confirmed locally advanced or metastatic EGFRm+ NSCLC harbouring an EGFR mutation known to be associated with EGFR TKI sensitivity and that is permitted in the osimertinib national label (such as exon 19 deletion and/or L858R), which is not amenable to curative therapy. --- L858R ---